Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 E Leigh Street, Richmond, VA 23298, United States.
Center for Substance Abuse Research and Department of Pharmacology, Lewis Katz School of Medicine, Temple University, 3500 North Broad Street, MERB 851, Philadelphia, PA 19140, United States; Beijing Key Laboratory of Neuropsychopharmacology, State Key Laboratory of Toxicology and Medical Countermeasures, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China.
Bioorg Chem. 2021 Apr;109:104702. doi: 10.1016/j.bioorg.2021.104702. Epub 2021 Feb 9.
In the present study, the role of 3-hydroxy group of a series of epoxymorphinan derivatives in their binding affinity and selectivity profiles toward the opioid receptors (ORs) has been investigated. It was found that the 3-hydroxy group was crucial for the binding affinity of these derivatives for all three ORs due to the fact that all the analogues 1a-e exhibited significantly higher binding affinities compared to their counterpart 3-dehydroxy ones 6a-e. Meanwhile most compounds carrying the 3-hydroxy group possessed similar selectivity profiles for the kappa opioid receptor over the mu opioid receptor as their corresponding 3-dehydroxy derivatives. [S]-GTPγS functional assay results indicated that the 3-hydroxy group of these epoxymorphinan derivatives was important for maintaining their potency on the ORs with various effects. Further molecular modeling studies helped comprehend the remarkably different binding affinity and functional profiles between compound 1c (NCP) and its 3-dehydroxy analogue 6c.
在本研究中，考察了一系列环氧吗啡喃衍生物中 3-羟基基团在与阿片受体（ORs）结合亲和力和选择性特征方面的作用。研究发现，由于所有类似物 1a-e 与相应的 3-去羟基类似物 6a-e 相比，均表现出显著更高的结合亲和力，因此 3-羟基基团对于这些衍生物与所有三种 ORs 的结合亲和力至关重要。同时，大多数带有 3-羟基基团的化合物在与κ型阿片受体相比时，对μ型阿片受体具有相似的选择性特征，就像它们相应的 3-去羟基衍生物一样。[S]-GTPγS 功能测定结果表明，这些环氧吗啡喃衍生物的 3-羟基基团对于维持其在 ORs 上的效力非常重要，且具有不同的作用。进一步的分子建模研究有助于理解化合物 1c（NCP）与其 3-去羟基类似物 6c 之间显著不同的结合亲和力和功能特征。
